Unveiling the role of cathepsins in depression: a Mendelian randomization study

Depression is a prevalent psychological disorder involving complex pathogenesis mechanisms. Cathepsins may play a significant role in the pathogenesis of depression, yet the exact impact of cathepsins on the risk of developing depression remains unclear. The objective of this research was to examine the cause-and-effect link between cathepsins and the susceptibility to depression through the application of Mendelian randomization (MR) techniques. Univariate MR, bidirectional MR, and multivariable MR were employed to study this causal relationship. Additionally, horizontal pleiotropy, heterogeneity, and sensitivity assessments were performed on the results obtained from MR. The univariate MR analysis indicated that elevated levels of cathepsin S increase the risk of depression. Conversely, the reverse MR analysis showed no causal relationship between depression, serving as an exposure dataset, and nine types of cathepsins. The multivariable MR analysis, based on nine types of cathepsins, revealed that increased expression levels of cathepsin S and F are associated with an increased risk of depression. A positive causal relationship has been identified between cathepsin S and cathepsin F and the risk of depression. Consequently, individuals exhibiting elevated levels of cathepsin S and F should be vigilant regarding their mental health to mitigate the potential risk of developing depression in the future. Key message What is already known on this topic Depression is a prevalent psychological disorder involving complex pathogenesis mechanisms. Cathepsins may play a significant role in the pathogenesis of depression, yet the exact impact of cathepsins on the risk of developing depression remains unclear. What this study adds This study presents the inaugural univariate and multivariate Mendelian randomization analysis examining the association between cathepsins and depression, identifying a positive causal relationship between cathepsins S and F and the risk of developing depression. How this study might affect research, practice, or policy Individuals exhibiting elevated levels of cathepsin S and F should prioritize monitoring their mental health to mitigate the potential risk of developing depression in the future.